Pharmaceutical formulation in the form of bilayered tablets comprising hmg-coa reductase inhibitor and irbesartan

Abstract

Provided is a pharmaceutical formulation in the form of a bilayered tablet consisting of a first layer containing irbesartan or a pharmaceutically acceptable salt thereof and a second layer containing an HMG-CoA reductase inhibitor and a basic additive, which can improve the dissolution rate and stability of irbesartan and an HMG-CoA reductase inhibitor to enhance the bioavailability of the drug compared to conventional complex formulations and to minimize the generation of the related compounds, thereby being effectively used as a stable and superior therapeutic agent for hypertension and hypercholesterolemia.

1 . A pharmaceutical formulation in the form of a tablet comprising:
 a) a first layer containing irbesartan or a pharmaceutically acceptable salt thereof; and   b) a second layer containing an HMG-CoA reductase inhibitor and a basic additive.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of rosuvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, pitavastatin, simvastatin, rivastatin, cerivastatin, velostatin, mevastatin, and pharmaceutically acceptable salts, precursors and mixtures thereof. 
     
     
         3 . The pharmaceutical formulation of  claim 2 , wherein the HMG-CoA reductase inhibitor is atorvastatin. 
     
     
         4 . The pharmaceutical formulation of  claim 1 , which exhibits dissolution profile such that 80% or more of each of irbesartan and the HMG-CoA reductase inhibitor is released within 30 minutes. 
     
     
         5 . The pharmaceutical formulation of  claim 4 , which exhibits dissolution profile such that 80% or more of each of irbesartan and the HMG-CoA reductase inhibitor is released within 15 minutes. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein the basic additive is selected from the group consisting of NaHCO 3 , CaCO 3 , MgCO 3 , KH 2 PO 4 , K 2 HPO 3 , tribasic calcium phosphate, arginine, lysine, histidine, meglumine, magnesium aluminum silicate, magnesium aluminum metasilicate, and a salt and a mixtures thereof. 
     
     
         7 . The pharmaceutical formulation of  claim 6 , wherein the basic additive is NaHCO 3 , MgCO 3  or a mixture thereof. 
     
     
         8 . The pharmaceutical formulation of  claim 1 , wherein the basic additive is included in an amount of 2 to 10 parts by weight based on 1 part of HMG-CoA reductase inhibitor. 
     
     
         9 . The pharmaceutical formulation of  claim 1 , wherein the basic additive is included in an amount of 0.2 to 10 parts by weight based on 1 part of irbesartan. 
     
     
         10 . The pharmaceutical formulation of  claim 1 , wherein the second layer of the formulation further comprises a water-soluble diluent selected from the group consisting of mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and mixtures thereof. 
     
     
         11 . The pharmaceutical formulation of  claim 1 , wherein the second layer of the formulation further comprises disintegrants, binders, carriers, fillers, lubricants, rheology modifiers, crystallization retarders, solubilizers, coloring agents, pH modifiers, surfactants, emulsifiers, coating agents, or mixtures thereof. 
     
     
         12 . The pharmaceutical formulation of  claim 1 , wherein the first layer of the formulation further comprises binders, disintegrants, lubricants or mixtures thereof. 
     
     
         13 . The pharmaceutical formulation of  claim 12 , wherein the binders are selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, starch, pregelatinized starch and mixtures thereof. 
     
     
         14 . The pharmaceutical formulation of  claim 12 , wherein the disintegrants are selected from the group consisting of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, sodium carboxyl methyl starch, starch and mixtures thereof. 
     
     
         15 . The pharmaceutical formulation of  claim 12 , wherein the lubricant are selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate or stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, and mixtures thereof. 
     
     
         16 . The pharmaceutical formulation of  claim 1 , wherein the formulation comprises irbesartan or a pharmaceutically acceptable salt thereof in an amount of 8 mg to 600 mg per unit dosage form. 
     
     
         17 . The pharmaceutical formulation of  claim 1 , wherein the formulation comprises the HMG-CoA reductase inhibitor in an amount of 0.5 mg to 100 mg per unit dosage form. 
     
     
         18 . The pharmaceutical formulation of  claim 1 , wherein the formulation further comprises surfactants in the first layer. 
     
     
         19 . The pharmaceutical formulation of  claim 18 , wherein the surfactants are selected from the group consisting of sodium lauryl sulfate, poloxamer, polyethylene glycol, and mixtures thereof. 
     
     
         20 . A method for preparing the pharmaceutical formulation in the form of a tablet of  claim 1 , comprising the steps of:
 (i) granulating irbesartan or a pharmaceutically acceptable salt thereof to obtain granules for a first layer;   (ii) granulating a mixture of an HMG-CoA reductase inhibitor and a basic additive to obtain granules for a second layer; and   (iii) compressing the granules for the first layer and the second layer into a bilayered tablet.